title: Somatic copy number changes in DPYD are associated with lower risk of recurrence in triple-negative breast cancers.
abstract: BACKGROUND
  Genomic rearrangements at the fragile site FRA1E may disrupt the dihydropyrimidine dehydrogenase gene (DPYD) which is involved in 5-fluorouracil (5-FU) catabolism. In triple-negative breast cancer (TNBC), a subtype of breast cancer frequently deficient in DNA repair, we have investigated the susceptibility to acquire copy number variations (CNVs) in DPYD and evaluated their impact on standard adjuvant treatment.
  
  
  METHODS
  DPYD CNVs were analysed in 106 TNBC tumour specimens using multiplex ligation-dependent probe amplification (MLPA) analysis. Dihydropyrimidine dehydrogenase (DPD) expression was determined by immunohistochemistry in 146 tumour tissues.
  
  
  RESULTS
  In TNBC, we detected 43 (41%) tumour specimens with genomic deletions and/or duplications within DPYD which were associated with higher histological grade (P=0.006) and with rearrangements in the DNA repair gene BRCA1 (P=0.007). Immunohistochemical analysis revealed low, moderate and high DPD expression in 64%, 29% and 7% of all TNBCs, and in 40%, 53% and 7% of TNBCs with DPYD CNVs, respectively. Irrespective of DPD protein levels, the presence of CNVs was significantly related to longer time to progression in patients who had received 5-FU- and/or anthracycline-based polychemotherapy (hazard ratio=0.26 (95% CI: 0.07-0.91), log-rank P=0.023; adjusted for tumour stage: P=0.037).
  
  
  CONCLUSIONS
  Genomic rearrangements in DPYD, rather than aberrant DPD protein levels, reflect a distinct tumour profile associated with prolonged time to progression upon first-line chemotherapy in TNBC.
authors.affiliation: Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Gross
authors.forename: C
authors.initials: C
authors.lastname: Meul
authors.forename: S
authors.initials: S
authors.lastname: Raab
authors.forename: C
authors.initials: C
authors.lastname: Propping
authors.forename: S
authors.initials: S
authors.lastname: Avril
authors.forename: M
authors.initials: M
authors.lastname: Aubele
authors.forename: A
authors.initials: A
authors.lastname: Gkazepis
authors.forename: T
authors.initials: T
authors.lastname: Schuster
authors.forename: N
authors.initials: N
authors.lastname: Grebenchtchikov
authors.forename: M
authors.initials: M
authors.lastname: Schmitt
authors.forename: M
authors.initials: M
authors.lastname: Kiechle
authors.forename: J
authors.initials: J
authors.lastname: Meijer
authors.forename: R
authors.initials: R
authors.lastname: Vijzelaar
authors.forename: A
authors.initials: A
authors.lastname: Meindl
authors.forename: A B P
authors.initials: AB
authors.lastname: van Kuilenburg
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000235:genetics; D043283:Chromosome Fragile Sites / Q000187:drug effects; D056915:DNA Copy Number Variations; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D017353:Gene Deletion; D020440:Gene Duplication / Q000187:drug effects / Q000235:genetics; D015321:Gene Rearrangement / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011859:Radiography; D064726:Triple Negative Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil